This invention relates to a process for the selective synthesis of stereoisomers. More particularly, this invention relates to a process for the stereoselective synthesis of enantiomers of nitriles and primary amines that are useful in the synthesis of (+)-physostigmine and (-)-physostigmine.
The cholinergic neuronal system can be found in the central nervous system (CNS), in the autonomic nervous system, and in the skeletal motor system. Acetylcholine (ACh) is the neurotransmitter in all ganglia, the neuromuscular junction, and the post-ganglionic synapses of the cholinergic nervous system. Acetylcholine is normally an excitatory neurotransmitter that binds to nicotinic and muscarinic receptors.
Acetylcholinesterase (AChE) is an enzyme that hydrolyzes and thereby deactivates ACh after it binds to a receptor. This enzyme is present in all peripheral and central junctional sites and in certain cells of the body.
In some circumstances, it is desirable to stimulate acetylcholine receptors. One method involves the use of indirect agonists, such as anticholinesterase drugs, which inhibit the hydrolysis of ACh by AChE. When an anticholinesterase drug blocks AChE and inhibits the destruction of released ACh, a higher neurotransmitter level and increased biological response result. The alkaloid, physostigmine, which can be isolated from the seeds of the Calabar bean, has been found to be particularly effective as an anticholinesterase drug. Physostigmine has a high affinity for AChE and is capable of inhibiting AChE for prolonged periods.
It is believed that degeneration of the cholinergic pathways in the CNS and the resultant development of apparent irregularities in neuron arrangement may be a principal cause of senile dementia of the Alzheimer type. This disease leads to progressive regression of memory and learned functions. Since the average age of the population is on the increase, the frequency of Alzheimer's disease is increasing and requires urgent attention.
It has been suggested that cholinergic agonists, such as the anticholinesterase drugs, are useful in the treatment of Alzheimer's disease. Nevertheless, drug treatment with anticholinesterase drugs has not proved entirely satisfactory. Thus, there is a need in the art for new forms of drugs for the treatment of this disease.
The enantiomers of physostigmine and pharmaceutically active physostigmine-like compounds, such as the compounds described in U.S. Pat. No. 4,791,107, are under investigation for the treatment of Alzheimer's disease. In order to satisfy the need for compounds having the highest pharmaceutical activity, there exists a need in the art for a process for the stereoselective synthesis of the enantiomers. Specifically, the enantiomer (-)physostigmine is of current interest, and while methods for preparing physostigmine and physostigmine-like compounds have been proposed, there exists a need in the art for a stereoselective process for producing the S- or (-)-forms.
It has been found that the compound 1,3-dimethyl-5-methoxyoxindolylethylamine, also referred to as 3-(2-aminoethyl)-1,3-dihydro-1,3-dimethyl-5-methoxy-2H-indol-2-one, is an important intermediate in a recently discovered method of synthesizing (-)-physostigmine. While this amine can be prepared using conventional techniques, a racemic mixture is usually formed. Resolution of the racemic amine mixture into its R and S components makes it possible to synthesize (+)-physostigmine and (-)-physostigmine.
A process for the stereoselective synthesis of the amines and their precursors could provide certain advantages. Such a process could reduce or eliminate the need for resolving mixtures of enantiomers. While stereoselective syntheses that are catalyzed by enzymes are highly enantioselective, non-enzymatic processes have a wide range of selectivity. Accordingly, the results obtained in processes based on synthetic chemical techniques are generally unpredictable, and successful results in stereoselective syntheses have been difficult to achieve.
Thus, there exists a need in the art for methods based on chemical techniques for producing enantiomers of physostigmine and physostigmine-like compounds. There also exists a need in the art for methods for the asymmetric synthesis of intermediates for use in the process. The method should make it possible to obtain the intermediates in a state of high optical purity. In addition, the process should be easy to carry out and should employ reagents that are readily available.